Normal Brain Activity Linked to DNA Damage

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Brain activity from experiences as common as exploring new
locations surprisingly damages the noggin's DNA, hinting that
such disruptions may be a key part of thinking, learning and
memory, researchers say.

This damage normally heals rapidly, but abnormal proteins seen in
Alzheimer's disease can increase this damage further, perhaps
overwhelming the ability of brain cells to heal it. Further
research into preventing this damage might help treat
brain disorders, scientists added.

Explorer mice

Scientists analyzed young adult mice after they were placed into
new, larger cages with different toys and odors that they were
allowed to explore for two hours. They measured brain levels of a
protein known as gamma-H2A.X, which accumulates when breaks occur
in double-stranded molecules of DNA.

"DNA comes in double strands, and has the shape of a twisted
ladder," said researcher Lennart Mucke, a neurologist and
neuroscientist at the Gladstone Institute of Neurological Disease
and the University of California at San Francisco. "Breaks in one
strand, in one rail of the ladder, occur quite frequently, but
breaking both takes quite a bit of damage and, in the brain, was
thought to happen mostly in the context of disease." [ 10
Odd Facts About the Brain ]

Unexpectedly, the researchers found such breaks also happened in
the neurons of perfectly healthy mice, with up to six times more
breaks in the neurons of explorer mice than in mice that remained
in their home cages.

"Breaks of double strands of DNA seem to be a part of normal
healthy brain activity," Mucke told LiveScience.

These DNA breaks occurred in various brain regions, especially in
the dentate gyrus, an area necessary for spatial memory.

"It is both novel and intriguing, [the] team's finding that the
accumulation and repair of DSBs [double-strand breaks] may be
part of normal learning," said neuroscientist Fred Gage, of the
Salk Institute, who did not take part in this study.

Mystery of DNA breaks

It remains uncertain why brain activity causes DNA breaks. Active
neurons do generate DNA-damaging chemicals such as free radicals,
but neurons in lab dishes did not have significantly fewer breaks
when given antioxidant molecules that counteract free radicals.

Instead, the researchers suggest these breaks could actually help
with the genetic activity linked with mental activity.

"We are now very excited to explore why neuron activity causes
these
breaks in DNA — whether these breaks somehow facilitate the
rapid conversion of genes into proteins involved in memory and
learning and in processing all the information you take in when
you do something new," Mucke said.

Many of the DNA breaks were fixed within 24 hours via DNA repair
mechanisms in the cells. However, mice genetically engineered to
produce a protein fragment known as amyloid beta, which
accumulates in the brains of Alzheimer's patients, had more DNA
breaks than normal in their brains, a problem that worsened
during exploration.

Mice that produce human amyloid beta in their brains often have
abnormal brain activity, including epileptic seizures, which can
also occur in Alzheimer's patients. The researchers found that
blocking this
abnormal brain activity with the widely used
anti-epileptic drug levetiracetam reduced the number of DNA
breaks in the neurons of these mice.

"Levetiracetam is already an FDA-approved drug, and a very small
clinical trial has already shown that it could provide some
benefits in people with early-stage Alzheimer's," Mucke said.
"These findings support the idea that the drug might be able to
modify the disease by preventing the accumulation of DNA breaks
that may promote its progress."

"We're in the process now of designing a larger-scale carefully
controlled clinical trial to see if such a strategy is of
benefit," Mucke added. "We encourage people to wait until this
data becomes available and not jump the gun and start taking this
drug when it hasn't been validated thoroughly yet."

The scientists also found that when mice lacked a protein known
as tau, excess amyloid beta no longer caused more DNA breaks.

"Tau is intimately involved with Alzheimer's — it seems to
cooperate with amyloid beta," Mucke said. "In the absence of tau,
amyloid beta doesn't seem to elicit detrimental effects. We're in
the process of developing strategies to manipulate tau in
Alzheimer's, and these findings encourage us to intensify and
accelerate these efforts."

The scientists detailed their findings online March 24 in the
journal Nature Neuroscience.